US5744464A - Antigestagens for the inhibition of uterine synthesis of prostaglandin - Google Patents

Antigestagens for the inhibition of uterine synthesis of prostaglandin Download PDF

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Publication number
US5744464A
US5744464A US08/096,360 US9636093A US5744464A US 5744464 A US5744464 A US 5744464A US 9636093 A US9636093 A US 9636093A US 5744464 A US5744464 A US 5744464A
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US
United States
Prior art keywords
beta
alpha
hydroxy
dimethylamino
phenyl
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US08/096,360
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English (en)
Inventor
Walter Elger
Krzysztof Chwalisz
Sybille Beier
Marianne Fahnrich
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Bayer Pharma AG
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Schering AG
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Priority to US08/096,360 priority Critical patent/US5744464A/en
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Publication of US5744464A publication Critical patent/US5744464A/en
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Expired - Lifetime legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates to the use of antigestagens and the production of drugs containing antigestagens for the inhibition of uterine synthesis of prostaglandin, especially for the treatment and prevention of dysmenorrheic symptoms.
  • RU 486 11-beta- 4-N, N-dimethylamino)-phenyl!-17-beta-hydroxy-17-alpha-propinyl-4, 9(10)-estradien-3-one designated as RU 486.
  • Data on the therapeutic mechanism of RU 486 are found in "Human Reproduction,” Vol. 1 (1986), 107-110.
  • antigestagen causes a blocking of progesterone activity and an increase of the formation of prostaglandin, and the prostaglandin stimulates uterine contractility.
  • RU 486 clinical studies to the end of pregnancy have just been conducted.
  • the invention further relates to the use of antigestagens for treatment and prevention of dysmenorrheic symptoms.
  • Inhibition of uterine PG through the use of antigestagens eliminates or at least substantially lessens the symptoms which accompany dysmenorrhea. Since uterine synthesis of PG occurs essentially in the endometrium, disturbances and pains resulting from endometriosis will also be beneficially affected by antigestagens.
  • the advantage of this treatment course is that a desirable degree of inhibition is attained without affecting the PG function in other organs.
  • a high degree of organ selectivity is achieved through the treatment of dysmenorrhea with antigestagens.
  • Antigestagens can be used at the onset of dysmenorrheic symptoms, such as "pains in the lower abdomen.” It is sometimes appropriate to set the beginning of the treatment at somewhat earlier phases of the luteal phase to achieve a sufficient degree of inhibition. In such prophylactic treatment, typical hosts are those with a prior history of dysmenorrheic symptoms, and treatment is commenced before the onset of estrus or menstruation.
  • the antigestagen treatment is given as a rule over 1 to 6, preferably 1 to 4 days, preferably starting at the beginning of the estrual or menstrual period or upon the appearance of symptoms.
  • progesterone receptor As antigestagens, all compounds which have a strong affinity for the gestagen receptor (progesterone receptor) and at the same time show no gestagenic activity of their own are suitable.
  • progesterone receptor As competitive progesterone antagonists, the following steroids, for example, are suitable:
  • the antigestagens can, for example, be administered locally, topically, enterally or parenterally.
  • tablets, coated tablets, capsules, pills, suspensions or solutions which can be produced in the standard way with the admixtures and vehicles usual in galenic medicine are suitable.
  • vaginal suppositories or transdermal systems such as skin plasters, for example, are suitable.
  • the antigestagens are used generally in amounts of about 2 to 50 mg/day, preferably about 5 to 20 mg/day of 11-beta- (4-N,N-dimethylamino)-phenyl!-17-alpha-hydroxy-17-beta-(3-hydroxypropyl)-13-alpha-methyl-4, 9(10)-gonadien-3-one or in a biologically equivalent amount of another antigestagen.
  • Such amounts can be routinely determined by differential dosage studies using a conventional protocol determining antigestagenic activity; e.g. Fertility and Sterility 40,253 (1982), Steroids 37, 361 (1981).
  • the compounds according to this invention when administered to patients, e.g., humans to inhibit PG formation or treat dysmenorrhea can be used analogously to the known agent Cyclo-Progynova ®. Dosage amounts are analogous when administered to prevent dysmenorrhea.
  • 50 mg of the antigestagen is dissolved in 1 ml each of castor oil/benzyl benzoate in a 6:4 ratio by volume.
  • Nonpregnant guinea pigs received daily, from the 8th to the 16th day of theapproximately 16-day cycle, 10 mg of 11-beta- (4-N,N-dimethylamino)-phenyl!-17-alpha-hydroxy-17-beta-(3-hydroxypropyl)-13-alpha-methyl-4, 9(10)-gonadien-3-one.
  • the test substance was dissolved in 1 ml of benzyl benzoate/castor oil (1:2) and injected subcutaneously. The progesterone content of the serum was determined daily.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Urology & Nephrology (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
US08/096,360 1986-09-26 1993-07-26 Antigestagens for the inhibition of uterine synthesis of prostaglandin Expired - Lifetime US5744464A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US08/096,360 US5744464A (en) 1986-09-26 1993-07-26 Antigestagens for the inhibition of uterine synthesis of prostaglandin

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DE3633244.5 1986-09-26
DE19863633244 DE3633244A1 (de) 1986-09-26 1986-09-26 Antigestagene zur hemmung der uterinen prostaglandinsynthese
US10068287A 1987-09-24 1987-09-24
US58144490A 1990-09-10 1990-09-10
US08/096,360 US5744464A (en) 1986-09-26 1993-07-26 Antigestagens for the inhibition of uterine synthesis of prostaglandin

Related Parent Applications (1)

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US58144490A Continuation 1986-09-26 1990-09-10

Publications (1)

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US5744464A true US5744464A (en) 1998-04-28

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US08/096,360 Expired - Lifetime US5744464A (en) 1986-09-26 1993-07-26 Antigestagens for the inhibition of uterine synthesis of prostaglandin

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Country Link
US (1) US5744464A (enrdf_load_stackoverflow)
EP (1) EP0266303B1 (enrdf_load_stackoverflow)
JP (1) JP2582088B2 (enrdf_load_stackoverflow)
AT (1) ATE78690T1 (enrdf_load_stackoverflow)
AU (1) AU605177B2 (enrdf_load_stackoverflow)
DE (2) DE3633244A1 (enrdf_load_stackoverflow)
DK (1) DK169162B1 (enrdf_load_stackoverflow)
ES (1) ES2051766T3 (enrdf_load_stackoverflow)
GR (1) GR3005467T3 (enrdf_load_stackoverflow)
IE (1) IE66196B1 (enrdf_load_stackoverflow)
IL (1) IL83967A (enrdf_load_stackoverflow)
ZA (1) ZA877247B (enrdf_load_stackoverflow)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6096732A (en) * 1996-12-06 2000-08-01 Schering Ag Steroid esters, process for their production and their pharmaceutical use
US20100249125A1 (en) * 2009-03-31 2010-09-30 The Texas A&M University System Inhibition of prostglandin e2 receptors for the treatment of endometriosis

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3733478A1 (de) * 1987-10-01 1989-04-13 Schering Ag Antigestagen- und antioestrogenwirksame verbindungen zur geburtseinleitung und zum schwangerschaftsabbruch sowie zur behandlung gynaekologischer stoerungen und hormonabhaengiger tumore
FR2651435A1 (fr) * 1989-09-07 1991-03-08 Roussel Uclaf Nouvelle utilisation de composes anti-progestomimetiques.
FR2654337B1 (fr) * 1989-11-15 1994-08-05 Roussel Uclaf Nouvelles microspheres injectables biodegradables procede de preparation et suspensions injectables les renfermant.
CO5200772A1 (es) 1999-08-31 2002-09-27 Jenapharm Gmbh And Co Kg Mesoprogestinas (moduladores de receptores de progesterona) para el trataiento y la prevencion de transtornos ginecolo- gicos benignos hormona-dependientes

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3077437A (en) * 1957-07-29 1963-02-12 George P Heckel Pregnanediol for treatment of premenstrual syndrome
US3666858A (en) * 1967-06-29 1972-05-30 Gordon Alan Hughes Utilization of gon-4-ene therapy in treatment of females and in growth stimulation
EP0139608A2 (de) * 1983-10-12 1985-05-02 Schering Aktiengesellschaft Prostaglandine und Antigestagene zur Geburtseinleitung oder für den Schwangerschaftsabbruch
EP0147361A2 (de) * 1983-12-22 1985-07-03 Schering Aktiengesellschaft 11 Beta-Aryl-Estradiene, deren Herstellung und diese enthaltende pharmazeutische Präparate
US4780461A (en) * 1983-06-15 1988-10-25 Schering Aktiengesellschaft 13α-alkyl-gonanes, their production, and pharmaceutical preparations containing same
US4814327A (en) * 1986-07-25 1989-03-21 Schering Aktiengesellschaft 11 β-(4-isopropenylphenyl)estra-4,9-dienes, their production, and pharmaceutical preparations containing same
US4870069A (en) * 1987-01-23 1989-09-26 Schering Aktiengesellschaft 11β-alkynyl-estrenes and -estradienes, their production and pharmaceutical preparations containing them

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3077437A (en) * 1957-07-29 1963-02-12 George P Heckel Pregnanediol for treatment of premenstrual syndrome
US3666858A (en) * 1967-06-29 1972-05-30 Gordon Alan Hughes Utilization of gon-4-ene therapy in treatment of females and in growth stimulation
US4780461A (en) * 1983-06-15 1988-10-25 Schering Aktiengesellschaft 13α-alkyl-gonanes, their production, and pharmaceutical preparations containing same
EP0139608A2 (de) * 1983-10-12 1985-05-02 Schering Aktiengesellschaft Prostaglandine und Antigestagene zur Geburtseinleitung oder für den Schwangerschaftsabbruch
US4626531A (en) * 1983-10-12 1986-12-02 Schering Aktiengesellschaft Prostaglandins and antigestagens for induction of labor and for abortion
EP0147361A2 (de) * 1983-12-22 1985-07-03 Schering Aktiengesellschaft 11 Beta-Aryl-Estradiene, deren Herstellung und diese enthaltende pharmazeutische Präparate
US4609651A (en) * 1983-12-22 1986-09-02 Schering Aktiengesellschaft 11β-arylestradienes, their production, and pharmaceutical preparations containing same
US4814327A (en) * 1986-07-25 1989-03-21 Schering Aktiengesellschaft 11 β-(4-isopropenylphenyl)estra-4,9-dienes, their production, and pharmaceutical preparations containing same
US4870069A (en) * 1987-01-23 1989-09-26 Schering Aktiengesellschaft 11β-alkynyl-estrenes and -estradienes, their production and pharmaceutical preparations containing them

Non-Patent Citations (42)

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Baulieu et al, Human Reproduction, vol. 1, No. 2, pp. 107-110 (1986).
D.G. Porter, "The Failure of Porgesterone to Affect Myometrial . . . ", J. Endocr (1970), 46, 425-434.
D.G. Porter, The Failure of Porgesterone to Affect Myometrial . . . , J. Endocr (1970), 46, 425 434. *
Elger et al., Am. J. Obstet. Gynecol., vol. 157 (4Pt2), 1987 Oct., pp. 1065 1074. *
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F a hnrich, Acta Endocrinol Suppl , vol. 114 (Jun. 1987), p. 126. *
Fahnrich, Acta Endocrinol Suppl!, vol. 114 (Jun. 1987), p. 126.
G. Haluska et al., "Temporal changes in uterine activity and . . . ", Am J Obstet Gynecol, Dec. 1987, pp. 1487-1495.
G. Haluska et al., Temporal changes in uterine activity and . . . , Am J Obstet Gynecol, Dec. 1987, pp. 1487 1495. *
J. P. Wolf et al., "Progesterone antagonist (RU 486) for cervical . . . ", Am J Obstet Gynecol, Jan. 1989, pp. 45-47.
J. P. Wolf et al., Progesterone antagonist (RU 486) for cervical . . . , Am J Obstet Gynecol, Jan. 1989, pp. 45 47. *
Kettel et al., "Endocrine responses to long-term administration of . . . ", Gynecology-endocrinology, vol. 56, No. 3, Sep., 1991, pp. 402-407.
Kettel et al., Endocrine responses to long term administration of . . . , Gynecology endocrinology, vol. 56, No. 3, Sep., 1991, pp. 402 407. *
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L.M. Kettel et al., Society for Gynecologic Investigation Abstract, S136, Lont Term, Low Dose RU 486 in the Treatment of Endometriosis . *
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Neulen et al., Acta Endocrinol Suppl , vol. 114, 1987 (Jun. 2, 1987) pp. 7 8. *
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R. Frydman et al., "Labor Induction in Women at Term With . . . ", Obstetrice & Gynecology, vol. 80, No. 6, pp. 972-975.
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Shi Shai Qing et al., "PGFM and Sex Steroid Concentrations Throughout . . . ", Hormone Antagonists for Fertility Regulation, pp. 87-97.
Shi Shai Qing et al., PGFM and Sex Steroid Concentrations Throughout . . . , Hormone Antagonists for Fertility Regulation, pp. 87 97. *
The Merck Manual, Fifteenth Edition, pp. 1700 1713 (1987). *
The Merck Manual, Fifteenth Edition, pp. 1700-1713 (1987).
W. Elger et al., "Endometrial and myometrail effects of progesterone . . . ", Am J Obstet Gynecol, vol. 157, No. 4, Oct. 1987, pp. 1065-1074.
W. Elger et al., "Studies on Interactions of Antiprogestins With . . . ", Hormone Antagonists for Fertility Regulation, C.P. Puri ed., pp. 105-121.
W. Elger et al., "Studies on Labor-Conditioning and Labor-Inducing . . . ", Uterine Contractility, R. Garfield ed., Serono Symposia, USA, Uterine Contractility, R. Garfield ed., Serono Symposia, USA,.
W. Elger et al., "Studies on the Mechanism of Action of Antifertile . . . ", Acta Physiologica Hungarica, vol. 65(4), pp. 415-432 (1985).
W. Elger et al., Endometrial and myometrail effects of progesterone . . . , Am J Obstet Gynecol, vol. 157, No. 4, Oct. 1987, pp. 1065 1074. *
W. Elger et al., Studies on Interactions of Antiprogestins With . . . , Hormone Antagonists for Fertility Regulation, C.P. Puri ed., pp. 105 121. *
W. Elger et al., Studies on Labor Conditioning and Labor Inducing . . . , Uterine Contractility, R. Garfield ed., Serono Symposia, USA, Uterine Contractility, R. Garfield ed., Serono Symposia, USA,. *
W. Elger et al., Studies on the Mechanism of Action of Antifertile . . . , Acta Physiologica Hungarica, vol. 65(4), pp. 415 432 (1985). *
W. Elger, "Pharmacology of Parturition and Abortion", Anim Reprod Sci, 2 (1979) pp. 133-148.
W. Elger, Pharmacology of Parturition and Abortion , Anim Reprod Sci, 2 (1979) pp. 133 148. *
Willman et al., British Journal of Obstetrics and Gynaecology, vol. 83, No. 3, May 1976, pp. 337 341. *
Willman et al., British Journal of Obstetrics and Gynaecology, vol. 83, No. 3, May 1976, pp. 337-341.

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6096732A (en) * 1996-12-06 2000-08-01 Schering Ag Steroid esters, process for their production and their pharmaceutical use
US20100249125A1 (en) * 2009-03-31 2010-09-30 The Texas A&M University System Inhibition of prostglandin e2 receptors for the treatment of endometriosis

Also Published As

Publication number Publication date
JP2582088B2 (ja) 1997-02-19
JPS63101326A (ja) 1988-05-06
DK487287D0 (da) 1987-09-16
IE872578L (en) 1988-03-26
ES2051766T3 (es) 1994-07-01
ATE78690T1 (de) 1992-08-15
DE3633244A1 (de) 1988-03-31
GR3005467T3 (enrdf_load_stackoverflow) 1993-05-24
DK169162B1 (da) 1994-09-05
EP0266303A2 (de) 1988-05-04
AU605177B2 (en) 1991-01-10
DE3780757D1 (de) 1992-09-03
IE66196B1 (en) 1995-12-13
AU7895087A (en) 1988-03-31
EP0266303B1 (de) 1992-07-29
ZA877247B (en) 1988-03-28
DK487287A (da) 1988-03-27
IL83967A0 (en) 1988-02-29
IL83967A (en) 1992-11-15
EP0266303A3 (en) 1989-12-20

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